POS0563 INFLUENCE OF ACTIVE VERSUS PLACEBO CONTROL ON TREATMENT RESPONSES IN RANDOMIZED CONTROLLED TRIALS IN RHEUMATOID ARTHRITIS
Authors: N. M. Stimakovits, A. Kerschbaumer, J. S. Smolen, T. Stefanova, E. Chwala, D. Aletaha
Journal: Annals of the Rheumatic Diseases (2022)

Background Randomised placebo controlled double-blind clinical trials are the mainstay of testing drugs for efficacy and safety and ultimately drug approval in medicine. 1 They are performed to ensure the efficacy of the active intervention against the effects of interventions without expected efficacy (placebo). Patients have to be fully consented to the risk of being (randomly) allocated to placebo by good clinical practice guidelines. 2 Knowledge about this risk may reduce the expectations about efficacy on both the patient and the investigator side. Once many therapeutic options are available, active control interventions are often used as comparators instead of placebo in trials. In such studies, placebo effects are still in place by the mere expectation of a response, but one could hypothesise that the observable effect of each intervention may be higher simply because of patients’ awareness of an active treatment (i.e. no risk of placebo). Here we investigated this hypothesis by comparing the effects of active controlled trials versus placebo controlled trials on the efficacy for the same therapeutic intervention in patients with rheumatoid arthritis (RA), in a systematic approach using all published trials in the field. Objectives To assess whether there is a systematic difference in response rates when investigating treatments in randomised controlled trials (RCTs) with active control compared to placebo control in RA clinical trials. Methods A systematic literature search was performed. We identified and matched RCTs that used comparable regimens, patient populations, background therapy and outcome reporting, but were different in terms of control group (active or placebo). Included studies were explored for potential risk of bias and mixed-model logistic regression was used to estimate odds ratios (OR) for achieving an American College of Rheumatology (ACR) 20, 50 and 70% response at week 12 in active-controlled studies compared to corresponding placebo-controlled studies. Results 7477 studies were screened, 576 of which underwent detailed review. Finally, 39 studies (45 study arms) were included for analysis. ACR response rates were higher in active controlled trials. The OR for achieving an ACR response when investigating the same treatment was consistently higher in studies with active control group than in corresponding studies with placebo control group: ORs were 1.64 (95% Confidence Interval, CI: 1.44-1.86; p&lt;0.001) for ACR20 (Figure 1), 1.46 (95% CI: 1.28-1.71, p&lt;0.001) for ACR50 and 1.61 (95% CI: 1.28-2.02; p&lt;0.001) for ACR70 at week 12. Figure 1. Forest plot showing ORs (with 95% CI) of achieving an ACR20 response at week 12 in studies with active control compared to studies with placebo control. Conclusion A systematic difference in response rates favouring head-to-head trials compared to placebo-controlled trials exists in RA clinical trials. This finding calls for consideration when interpreting and planning clinical trials and has implications for patients, investigators, sponsors and regulatory agencies. References [1]Bothwell, L.E. and S.H. Podolsky, The Emergence of the Randomized, Controlled Trial. N Engl J Med, 2016. 375(6): p. 501-4. [2]World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama, 2013. 310(20): p. 2191-4. Acknowledgements The authors thank B. Bierbaumer for his assistance in building the underlying database for this project. Disclosure of Interests None declared.